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Researchers outline potential genetic drivers of phyllodes tumours

A new study from researchers at the University of Michigan Comprehensive Cancer Center characterises the genetic underpinnings of a rare type of breast tumour, offering the first comprehensive analysis of the molecular alterations in phyllodes tumours. The analysis uses next-generation sequencing techniques that allowed researchers to identify alterations in genes from archived tissue samples.

Phyllodes tumors are rare fibroepithelial tumours with variable clinical behavior accounting for a small subset of all breast neoplasms. They represent about 1% of all types of breast tumours. Little is known about the genetic alterations that drive their initiation and/or progression. Most are benign but they do have the potential to become metastatic. Currently, there are no good ways to reliably predict which tumours are likely to recur or spread after initial treatment. Once phyllodes tumours become metastatic, there are few effective treatments.

Scott Tomlins, MD, PhDImage credit: University of Michigan Health System

Researchers led by Dr Scott Tomlins, assistant professor of pathology at the University of Michigan Medical School looked at 15 samples of phyllodes tumours, pulled from archived tissue samples at the University of Michigan. The samples were equally divided according to their classification, with five considered benign, five borderline and five malignant. While still a small sample, it can be sufficient with a rare tumour to identify genetic clues to the tumour's biology.

In addition, loss-of-function mutations in p53, as well as, deleterious mutations in the tumour suppressors retinoblastoma (RB1) and neurofibromin 1 (NF1) were identified exclusively in malignant tumours. High-level copy number alterations were nearly exclusively confined to malignant tumours, including potentially clinically actionable gene amplifications in IGF1R and EGFR.

Therapies have already been developed against EGFR and IGF1R proteins and tested in other cancers. Results from this study support evaluating these therapies in phyllodes tumours.

MED12 is frequently mutated in all classifications of phyllodes tumours. This gene also plays a role in some rare gynaecological tumours that are related to phyllodes tumours. The researchers believe MED12 could be involved with tumour initiation.

"Even though phyllodes tumours are rare, it's important to have good treatment options for the aggressive cases. The first step is understanding the underlying biology of these tumors," Dr Tomlins says. "Further study and validation is needed, but our work has identified several promising targets involved in phyllodes tumors." Integrated genomic sequencing and mutational profiling in this study provide insight into the molecular origin of phyllodes tumours and indicates potential druggable targets in malignant disease.

The study was funded by A. Alfred Taubman Medical Research Institute at the University of Michigan. Dr Tomlins has a separate sponsored research agreement with Compendia Bioscience/Life Technologies/ThermoFisher Scientific that provides access to the sequencing panel used in this study. No other aspect of the study was supported by the company.